Painful Vaso-occlusive Events Research Articles

The role of prophylactic transfusion on the maternal and fetal outcomes in pregnant women with sickle cell disease: A systematic review and meta-analysis.

In the present review, we aimed to synthesize evidence from studies on the safety and effectiveness of prophylactic blood transfusion in pregnant women with sickle cell disease. To gather relevant information, we conducted systematic electronic searches of databases such as SCOPUS, Medline via PubMed, Web of Science, and Cochrane Central Register of Controlled Trials. We included both retrospective and prospective studies that examined the impact of prophylactic blood transfusions during pregnancy. The collected data were analyzed using Review Manager, version 5.3. The review included 15 cohort studies. The overall findings indicated a preference for the prophylactic blood transfusion group over the control group across several key parameters. Specifically, the prophylactic group demonstrated lower rates of maternal mortality (odds ratio [OR] = 0.33; 95% confidence interval [CI] = 0.10-1.13; P = .08), reduced incidence of vaso-occlusive painful events (OR = 0.31; 95% CI = 0.14-0.73; P = .007), fewer pulmonary complications (OR = 0.21; 95% CI = 0.08-0.53; P = .001), decreased perinatal mortality (OR = 0.35; 95% CI = 0.17-0.75; P = .03), and lower likelihood of preterm birth (OR = 0.67; 95% CI = 0.47-0.96; P = .02). Notably, statistically significant heterogeneities were observed in the pooled effect estimates. The present meta-analysis indicated that prophylactic blood transfusion in pregnant women with sickle cell disease may improve maternal and fetal outcomes. However, substantial variations in the methodology and transfusion protocols among the included studies limited the credibility of the current evidence supporting the routine clinical use of prophylactic transfusion for SCD during pregnancy.

Alkaline Phosphatase As a Marker for Acute Complications in Sickle Cell Disease

Background: Sickle cell disease (SCD) can result in complications affecting multiple organ systems, including renal, pulmonary, and central nervous system. Alkaline phosphatases (ALP) comprise a group of isoenzymes which function to catalyze the hydrolysis of inorganic phosphate monoesters, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal-5′-phosphate. Predominantly, serum ALP is derived from the liver and bone (1). An elevation in serum ALP primarily signifies hepatobiliary disorders, wherein cholestasis and bile duct damage results in increased enzyme synthesis as a compensatory mechanism. Increased ALP levels can also be an indication of bone disease associated with increased osteoblast activity (2). ALP has been linked to the severity of the pain crisis in SCD (3), and there is also evidence that ALP is a predictor for increased mortality risk in SCD (4-6). This study aims to investigate ALP as a biomarker of SCD severity and acute organ complications (VOE). Methods: This retrospective study included 252 patients aged 18 years or older with SCD who were admitted to the University of Illinois Chicago (UIC) hospital for the management of vasoocclusive pain events (VOEs) between July 1, 2017, and June 30, 2018. The study recorded the following complications during hospitalization: acute chest syndrome, acute kidney injury, acute liver injury, thrombotic or hemorrhagic stroke, deep vein thrombosis or thromboembolism, the need for transfer to the intensive care unit, the need for exchange blood transfusion, or death during hospitalization. Data analyses were performed using the Kruskal-Wallis test, Chi-square test, linear or a stepwise ordinal logistic regression analysis. Results: The median age of this cohort was 31 years (interquartile range 26-42 years), 36% were males and 72% had hemoglobin SS/Sβ0 with 33% on hydroxyurea. In this cohort, 105 patients experienced at least one complication during at least one hospitalization(s) within the one-year study period, while 147 were hospitalized but did not experience complications during the hospitalization (Table 1). A comparison of clinical characteristics between the two cohorts revealed that patients with complications had a higher prevalence of HgbSS/Sβ0-genotype; had higher ALP, total bilirubin, and AST concentrations; Patients with complications had a greater number of hospitalizations and longer length of stay in both the median length and the total length over the study period (Table 2). In a multivariable model comparing baseline characteristics, HgbSS/Sβ0-genotype and increased ALP levels at baseline were significant predictors of complications during hospitalization, after adjusting for other variables as listed in the table (Table 3). Furthermore, in a subgroup analysis of patients with HgbSS/Sβ0-genotype, this relationship was even stronger: higher baseline ALP levels were significantly associated with acute complications during the study period (OR 7.3, 95% CI: 2.2 - 24.1, p = 0.001). Summary: Our findings suggest that SCD patients with longer hospital stay and higher numbers of admissions tend to have acute complications during hospitalization. Individuals with the HgbSS/Sbeta0 genotype and higher levels of ALP are at an increased risk of developing acute complications, which could potentially account for the increased mortality risk associated with alkaline phosphatase reported by previous literature. K. Makris, C. Mousa, E. Cavalier, Alkaline Phosphatases: Biochemistry, Functions, and Measurement. Calcif Tissue Int112, 233-242 (2023).J. Masrour Roudsari, S. Mahjoub, Quantification and comparison of bone-specific alkaline phosphatase with two methods in normal and paget's specimens. Caspian J Intern Med3, 478-483 (2012).J. I. Brody, W. N. Ryan, M. A. Haidar, Serum alkaline phosphatase isoenzymes in sickle cell anemia. JAMA232, 738-741 (1975).J. J. Feld et al., Liver injury is associated with mortality in sickle cell disease. Aliment Pharmacol Ther42, 912-921 (2015).S. A. Curtis, N. Danda, Z. Etzion, H. W. Cohen, H. H. Billett, Longitudinal Analysis of Patient Specific Predictors for Mortality in Sickle Cell Disease. PLoS One11, e0164743 (2016).V. Sachdev et al., A phenotypic risk score for predicting mortality in sickle cell disease. Br J Haematol192, 932-941 (2021).

The Optimal Threshold for Hemoglobin S Percent Level While Performing Regular Blood Transfusion Therapy to Prevent Severe Vaso-Occlusive Pain Events in Children with Sickle Cell Anemia: A Secondary Data Analysis of Participants in the SIT Trial

Introduction: Children with sickle cell disease (SCD) often experience frequent severe acute vaso-occlusive pain events, unresponsive to FDA-approved therapies (hydroxyurea, L-glutamine, crizanlizumab) to decrease the severe acute vaso-occlusive pain event incidence rate. The ASH guidelines for pain management recommend regular blood transfusion therapy after FDA-approved therapies have failed to decrease the high rate of severe acute vaso-occlusive pain events ( The Journal of Pediatrics, 139(6), 785-789). However, unlike regular blood transfusion therapy for primary and secondary stroke prevention, for which the goal hemoglobin S (Hb S) level is ≤ 30% , no optimal Hb S threshold has been established to attenuate the severe acute vaso-occlusive pain event incidence rate. We tested the hypothesis that among children receiving regular blood transfusion therapy with a goal to keep the mean hemoglobin S level < 30%, participants that achieved a mean Hb S level < 30% would have lower rates of severe acute vaso-occlusive pain events requiring hospitalization than children regularly transfused with mean Hb S level > 30%. Evidence to support our hypothesis would provide the first evidence-based guidelines for the optimal hemoglobin S threshold to decrease the acute vaso-occlusive pain event incidence rate in children with sickle cell anemia (HbSS). Methods: The SIT trial was a single-blind clinical trial( Blood Advances, 4(12), 2656-2701), where participants were children with sickle cell anemia randomly allocated to receive regular blood transfusion therapy (transfusion group) or standard care (observation group). Participants receiving regular blood transfusion therapy from the SIT Trial were included in the secondary analysis. Eligibility criteria include participants between 5 and 15 years of age, with no history of stroke, one or more silent cerebral infarcts on magnetic resonance imaging, and a neurologic examination showing no abnormalities. The transfusion therapy goal was to keep the maximum Hb S level < 30%. For the ancillary study, participants were included only in the transfusion arm of the trial. The primary endpoint of this ancillary study was the incidence rate of hospitalization for vaso-occlusive pain episodes among those receiving only regular blood transfusion therapy. We conducted a zero-inflated negative binomial regression analysis to determine the association between the incidence rate for severe acute vaso-occlusive pain events requiring hospitalization and independent covariates, including age at the time of random allocation, sex, and mean hemoglobin S level (< 30% and > 30%). Results: A total of 90 participants received regular blood transfusion therapy in the SIT trial. Among participants transfused, 53 and 37 individuals had a mean Hb S level of < 30% and > 30%, respectively. The median time on transfusions for the groups with Hb S levels of < 30% and > 30% was 2.9 years for both groups. Among the participants, 10.8% (4/37) who had a mean Hb S < 30% and 20.8% (11/53) of those with a mean Hb S > 30% experienced at least one hospitalization for a severe acute vaso-occlusive pain event. The mean hemoglobin S levels in the < 30% and > 30% groups were 25.4% and 37.5%, respectively. The mean hospital rates for severe acute vaso-occlusive pain events in the two groups < 30% and >30% were 9.4 (95% confidence interval 9.4 - 17.2 person-years) and 29.2 per 100 person-years (95% confidence interval, 21.0 - 39.5 person-years), respectively, P = 0.078. In the multivariable analysis, the incidence rate ratio for severe acute vaso-occlusive pain events showed that there was no statistical difference between those with a mean Hb S level in groups < 30% and > 30%, 0.65; P=0.43. Children with a higher baseline hemoglobin level were more likely to achieve a mean hemoglobin S level < 30%. Conclusion: In children with sickle cell anemia, receiving regular blood transfusion therapy with the goal of keeping the mean hemoglobin S level < 30%, achieving a mean hemoglobin S level > 30% was as effective as a mean hemoglobin S level < 30 % in decreasing the incidence rate of severe acute vaso-occlusive pain events requiring hospitalization. Further studies are warranted to identify reliable measures of the efficacy of regular blood transfusion therapy for the reduction of acute vaso-occlusive pain events.

Perception of Nutrition in Adults with Sickle Cell Disease: Concept Elicitation of Nutritional Status and the Mini Nutrition Assessment

Introduction Sickle Cell Disease (SCD) is a genetic disorder that causes recurrent vaso-occlusive pain events, functional impairment, and nutritional deficiencies due to increased metabolic demands. Prior studies have highlighted nutritional issues in people with SCD, such as micronutrient and macronutrient deficiencies, low body mass index (BMI), and a recent rise in obese adults with SCD. In older adults in the general population, evaluation and management of nutritional status is essential since malnutrition can weaken the immune system and increase the risk of hospitalization and death. Despite the importance of nutrition, little is known about the best way to evaluate nutritional status in older adults with SCD. To identify a relevant yet efficient method to evaluate nutritional status, we conducted content elicitation interviews to describe how younger and older adults conceptualized nutrition. Based on the content of the interviews, we piloted a brief nutritional survey called the Mini Nutritional Assessment (MNA); a common nutritional measure in geriatric assessments. Methods As standard practice for concept elicitation, we conducted semi-structured interviews with adults SCD in 4 separate focus groups: two groups of young adults age 18-39 and two groups of older adults age ≥ 40 years. Participants were asked about their perception of the construct of nutrition as part of a longer concept elicitation interview assessing the content validity of the Sickle Cell Disease Functional Assessment (SCD-FA), which is the geriatric assessment for adults with SCD. After focus group transcripts were analyzed using rapid qualitative analysis, we administered the MNA to a separate cohort of adults with SCD, since its content on macronutrients and hydration was consistent with how adults with SCD conceptualized nutrition. The scores on the 6-item MNA-Short Form (MNA-SF) range from 0 to 14 with higher scores indicating better nutritional status. Scores 12-14 indicate a normal nutritional status, 8-11 indicate at risk for malnutrition, and 0-7 indicate a malnourished state. Results The 4 focus group interviews included 6 younger adults (age 18-39) and 8 older adults (age ≥ 40 years) with SCD. Participants were 57% females and 79% had severe SCD genotype (HbSS or HbSβnull-thalassemia). In the focus groups, participants described a healthy diet as one that included the major food groups, which were generally defined as protein, fruits and vegetables, and starches/carbs. The majority discussed the importance of adequate hydration to reduce the risk of pain crises. Additionally, participants reported trying to substitute water for soda, juice, and caffeine containing beverages. Many participants stated that a healthy diet involved limited processed foods and sugars. Despite knowledge of the characteristics of a “healthy” diet, some participants expressed difficulty maintaining this diet. Based on these qualitative results, we selected the MNA to evaluate nutrition since it included items on hydration and assessed intake of various food groups as described by focus group participants. We administered the MNA-SF to a cohort of 88 adults with SCD and 81 had complete data to score the MNA-SF. The mean score for the MNA-SF for all participants was 11.7 ± 1.8 (younger adults 11.6 ± 1.9 and older adults 11.9 ± 1.8; p= 0.44). The MNA-SF identified 40% (n=34) as being at risk of malnutrition [36% of older adults and 46% younger adults]. Two participants were identified as being malnourished (1 younger and 1 older adult). On remaining MNA items (Table 1), 25% of participants reported decreased food intake with 17% having only 1 meal/day. Most participants (85%) consumed ≥ 1 serving of protein/day and 75% had ≥ 2 servings of fruits or vegetables/day. Most participants (68%) drank > 5 cups of water/day. Results were similar for younger and older adults with SCD. Conclusion Data from the focus group interviews revealed that BMI and unintentional weight loss measures alone did not comprehensively capture how people with SCD perceived the concept of nutrition. Incorporating the MNA-SF enhanced measurement of the nutritional domain in the SCD-FA by capturing data on food intake and hydration. In future studies we will assess the construct validity of the full MNA in a larger sample to identify older adults with SCD who would benefit most from nutritional interventions.

In Phase 2 and Phase 3 Trials, Broadening the Definition of Acute Vaso-Occlusive Pain to Include at Least One Episode of Pain Requiring Nsaids, Opioids, or Both Treatments at Home within 30 Days of a Physician Visit

Introduction:Despite the high incidence of acute painful events in children and adults with SCD, there is a lack of consensus on the acute pain definition in controlled clinical trials. To address this limitation, we elected to have three definitions of acute vaso-occlusive pain based on the setting for the pain location: inpatient, outpatient, ED, or at home. Based on the results of the SPRING Trial, the primary stroke prevention trial in children with SCD conducted in Nigeria (The Lancet Haematol. 2022 Jan 1;9(1):e26-37), and the PISCES study (Annals of internal medicine. 2008 Jan 15;148(2):94-101), most acute pain events in low-middle and high-income countries occur at home. We tested the hypothesis that the majority of negative phase 2 and phase 3-controlled trials for SCD failed to consider acute pain events in all four settings. Methods: To identify the relevant Phase II and III trials with acute pain as an outcome, we conducted a literature review using the website clinicaltrials.gov with the following key terms: “Sickle Cell Disease,” and “Vaso-occlusive.”. Studies that were not Phase II or Phase III were excluded from our search. We identified Phase 2 or 3 SCD pain trials published between 2015 and 2023. Inclusion criteria: definitions in the clinicaltrials.gov trial page, protocol, or method section. An inclusive, consensus definition for vaso-occlusive pain was chosen from the SPRING Trial. This definition was compared to the acute vaso-occlusive pain definitions of both SCD Phase 2 and 3 trials, with vaso-occlusive pain as a primary or secondary outcome. Based on the SPRING Trial and the results of the PISCES study, we elected to have three definitions of acute vaso-occlusive pain: 1. inpatient uncomplicated pain that excludes a concomitant diagnosis of acute chest syndrome; 2. Pain that required either an inpatient or outpatient visit and opioid treatment; and 3. An acute pain event at home requiring NSAIDs, opioids, or both. Only uncomplicated pain events were included to avoid double counting participants who developed acute chest syndrome or strokes that may have preceded the vaso-occlusive pain event. Results: We identified 35 articles based on our criteria. Our study sample included 3 clinical trials that led to the FDA approval for therapy to prevent acute vaso-occlusive pain events (FDA-approved therapy trials). Among these 35 trials, 32 clinical trials did not provide any evidence of the therapeutic benefits of the experimental agent (negative controlled trials). The three randomized controlled trials that led to FDA approval for therapy to prevent acute pain were: Hydroxyurea, L-Glutamine, and Crizanlizumab. Hospitalization for pain was included in all three FDA-approved therapy trials and 34.4% (11/32) of negative controlled trials. The ED visits in the pain definition were included in all 3 FDA-approved therapy trials and 28.1% (9/32) of negative controlled trials. Outpatient visits in the pain definition were included in all 3 FDA-approved therapy trials and 21.9% (7/32) of negative controlled trials. Home pain episodes were included in none of the FDA-approved therapy trials and 9.4% (3/32) of negative controlled trials. Finally, 43.8% (14/32) negative controlled trials were excluded as they failed to define vaso-occlusive pain in their methods or definition section and 15.6% (5/32) negative controlled trials did not have a publication. Conclusion: Most controlled trials designed to evaluate the efficacy of new treatment did not include the setting where pain occurs most frequently, at home. For future therapeutic trials designed to address whether a new therapy decreases the incidence rate of acute pain, we recommend an assessment of pain in all 4 four settings (Hospitalization, ED, Outpatient, and Home).

Hospitalizations among children with sickle cell disease enrolled in the Kumasi Sickle Cell Pan African Consortium (SPARCo) database: A cross sectional study.

Sickle cell disease (SCD) is the commonest monogenic haemolytic disorder in Africa. Despite strides made in its management, a significant proportion of patients are hospitalized from the various complications of the disease. This study set out to describe the main causes and outcomes of hospitalizations among pediatric patients with SCD. A cross-sectional study was conducted at the Pediatric Emergency Unit of Komfo Anokye Teaching Hospital within a period of 12 months to recruit pediatric SCD patients. This study looked at causes of admission, length of hospital stay (LOS), and outcome of admission. Of the 201 SCD patients recruited, 57.2% were males and majority were of SCD-SS phenotype 83.1%. The median age was 6 years. The three leading causes of hospitalization were Vaso-occlusive pain events (VOPE) (39.8%), acute chest syndrome (ACS) (25.9%), and infections (12.4%). Ten (5.0%) of the patients presented with a stroke. High admissions were observed in June (12.4%) and November (16.9%). The median (interquartile range [IQR]) LOS was 6 days (IQR: 4-10). Six (3.0%) of the patients died from complications of the disease during hospitalization. VOPE, ACS, infections, and acute anaemia from hyperhaemolysis were observed as the most common causes of admissions among SCD patients. A good outcome of discharge was seen in most of the patients that were hospitalized with a median length of stay of 6 days. This study also strengthens the importance of a good SCD database with patient follow-ups for better outcomes in SCD patients.

A Qualitative Systematic Review of Pediatric Patient and Caregiver Perspectives on Pain Management for Vaso-Occlusive Episodes in the Emergency Department.

The primary objective of this study is to describe the experiences of pediatric patients with sickle cell disease (SCD) and their caregivers who have presented to the emergency department (ED) for management of vaso-occlusive pain events. We conducted a qualitative systematic review. The search protocol was developed to identify both published and unpublished literature that met inclusion/exclusion criteria. Included articles were primary hospital-based research with study populations that included (but were not limited to) pediatric patients aged 21 years or younger and qualitative or mixed-method analysis. Four themes were identified: (1) patients and caregivers perceive the ED as the last resort; (2) health care professionals in the ED lacked knowledge about SCD but rejected patients' and caregiver's attempts to share experience or advocate for their needs; (3) patients' accounts of pain are doubted because they do not always have "typical" signs of pain; and (4) caregivers identify racism as a reason for suboptimal care in the ED. There are multiple opportunities to improve management for vaso-occlusive pain events in the ED, including education of health care providers about SCD and complications, partnership between patients/caregivers and providers, and efforts to reduce the impact of systemic racism on health care delivery.

Characterizing Frailty in Adults with Sickle Cell Disease Using Frailty Phenotype

Background As individuals with sickle cell disease (SCD) age, they acquire both SCD and age-related complications early in life leading to premature functional decline. Chronologic age does not accurately represent health status. Frailty is a syndrome that frequently occurs with aging, characterized by decreased physiologic reserve and increased vulnerability to stressors. It leads to adverse outcomes such as loss of independence and death. Individuals with SCD experience stressors such as frequent hospitalizations for vaso-occlusive painful events and organ damage; however, frailty has not been defined in people with SCD. This study seeks to assess the feasibility of characterizing frailty in older adults with SCD using the Fried Frailty Phenotype (FP). Methods We enrolled younger (age 18-39) and older (age ≥ 40 years) adults with SCD in a single-center cross-sectional study. Frailty was defined as the presence of ≥ 3 of the following criteria: unintentional weight loss (≥ 10 pounds in the last year), exhaustion (by 2-item questionnaire), weakness (seated grip strength < 27 kg for males and < 16 kg for females), slowness (usual gait speed ≤ 0.8 m/s), and low physical activity by questionnaire (energy expenditure < 383 kcal/week for men and < 270 kcal/week for women). Individuals with 1 or 2 criteria present were categorized as 'prefrail' and individuals with none of the criteria were categorized as 'robust'. We summarized demographic, medical history, and scores for each FP criterion. Feasibility end points were the proportion of participants who completed all portions of the FP assessment, acceptability of the assessments, and adverse events. We described the characteristic of participants in each FP group. Results We assessed FP at steady state in 28 participants. 93% (n=26) of participants had complete data (1 did not complete all surveys and 1 did not complete grip strength assessment both due to limited time in clinic). There were no adverse events related to performing FP. No participants reported that FP measures were difficult to understand or upsetting. The mean age of all participants was 46.3 (range 19-77 years). The mean age was 28.8 (± 5.1) for younger adults and 54.6 (± 8.7) for older adults. Most (68%) were aged ≥ 40 years and female (71%). Most (57%) had HbSS, 32% had HbSC, 7% had HbSβ0-thalassemia, and 4% had HbSβ+-thalassemia. Out of the 26 participants with complete data, 1 participant met criteria for being frail, 58% (n=15) were prefrail, and 38% (n=10) were robust. The proportion of participants positive for each FP criterion is shown in Figure 1. Out of the 27 participants who completed survey data, 7% (n=4) met criteria for weight loss. Several (41%) participants met criteria for exhaustion with 11 participants reporting that they felt that "everything was an effort" and 3 participants reported that they also felt that they "could not get going" at least a moderate amount of the time. The median grip strength was 30 kg (IQR 25-37) with median of 26 kg (IQR 21-32) for women and 53 kg (IQR 42-51) for men. No participants met criteria for weakness. On usual gait speed assessment, the median gait speed was 1.17 m/s (IQR 1.02-1.22). No participants met criteria for slowness. When we compared characteristics between prefrail/frail versus robust participants (Table 1), prefrail/frail participants had a significantly shorter six-minute walk distance (6MWD) (414 vs 492 meters; p=0.03) and had more participants hospitalized in the last year that approached significance (38% vs 0%; p=0.053). There was no difference in age, income, employment status, hemoglobin, hydroxyurea use, opioid use, history of avascular necrosis, or history of stroke. Conclusion We demonstrated that measuring frailty using Fried Frailty Phenotype was feasible, acceptable, and safe in both younger and older adults with SCD. Most participants met criteria for being prefrail due to exhaustion. Prefrail/frail participants in our study had a shorter 6MWD and more participants hospitalized in the last year, which suggests there is clinical significance in identifying prefrail individuals with SCD. This may facilitate early initiation of interventions to prevent frailty. Regular exercise has been shown to reduce exhaustion and frailty in older adults in the general population. In future studies we will assess the prevalence of frailty in a large sample of adults with SCD and determine the appropriate cut points for each criterion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sustained Improvements in Patient-Reported Quality of Life up to 24 Months Post-Treatment with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Sustained Improvements in Patient-Reported Quality of Life up to 24 Months Post-Treatment with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

A Resident-Led Quality Improvement Initiative to Optimize Care for Children and Young Adults with Sickle Cell Disease Vaso-Occlusive Pain with Intranasal Fentanyl in the Emergency Department

Background:Sickle cell disease (SCD) is an inherited blood condition that predisposes affected patients to severe vaso-occlusive (VOC) pain events. The NHLBI (last revised in 2014) and ASH guidelines (last revised 2020) recommend a door-to-first dose should be within 60 minutes vs. 30 minutes from registration, and reassessment and re-administration of medications should be every 30 minutes. Non-IV routes of administration, i.e. intranasal (IN) can facilitate rapid analgesic treatment. Recent studies have shown IN Fentanyl as an effective pharmacological strategy to treat vaso-occlusive pain episodes.Methods:This resident-led Quality Improvement specific aim was to reduce the meantime from check-in to first analgesic delivery to SCD patients with VOC presenting to the Pediatric Emergency Department (PED) by at least 20% during 12 months and to improve the overall care of SCD VOC in accordance to best practices.PDSA cycle methodology was utilized to identify root causes, countermeasures, and key drivers (Figure 1A). We implemented a SCD VOC clinical pathway for PED providers to utilize our enhanced and updated version of an electronic order set named “PED Sickle Cell Crisis Power Plan” that includes IN Fentanyl as first-line therapy for SCD VOC. IRB approval was obtained.PED nursing staff was trained to administer IN Fentanyl with a nasal mucosa atomizer. Exclusion criteria of patients with SCD with other ICD-10 diagnosis codes, i.e pain not associated with VOC. The main indicators were assessment-to-dose time; registration-to-discharge time; first dose-to-discharge time, and rate of VOC admissions. Data was collected by discrete-time stamps and statistically analyzed using Excel 365. The analysis compared baseline with initial PDSA cycles from December 2019 to February 2020, and from September 2020 to March 2021.Results:From September 2020 to February 2021, a total of 54 encounters for SCD VOC qualified clinically to receive IN Fentanyl. A total of 49 of these encounters received this medication, while 5 refused its administration.Patient demographics: Male-to-female ratio was 53% and 47%, respectively. The majority of the patients seen were adolescents (63% with ages between 12-21 years). African-American participants represented 88% and non-Hispanics 84%.After our interventions, 94% of encounters have documented pain reassessment in their electronic medical records. IN Fentanyl was first introduced in the PED in September 2020, and became the first medication to be administered in 94% of the encounters. The average length of stay in the PED was 269 minutes (4 hrs. with 29 minutes).The SCD VOC Clinical Pathway was used in 90% of the encounters and the SCD VOC Power Plan was used in 80% of them. From the total of encounters, 59% required admission to the floor for further pain management strategies.As shown in the control chart (Figure 1.B), the meantime from check-in to first analgesic delivery to patients with VOC presenting to the PED was reduced to under 40 minutes by February 2021.After the implementation of IN Fentanyl, there is an overall improvement of the waiting time for administration of medications of more than 70 minutes (from 138 min down to 67 minutes). Most importantly, 37% (18/49) of SCD VOC events were discharged after successful VOC pain management in the PED.Discussion:PED staff surveys demonstrated a lack of familiarity with current VOC guidelines and a standardized pathway. Medication refusal of IN Fentanyl was found to be related mostly to patient preference, poor knowledge about side effects, and parental fear for oversedation before our interventions.Conclusion:A multi-disciplinary team was formed to assist health care providers in the ED to deliver optimal care to patients with SCD based on the current evidence-based SCD VOC clinical pathway and efficient pharmacological intervention with IN Fentanyl.Standardized procedures to treat and reassess pain for SCD VOC patients in the PED resulted in check-in to first-dose time reduction by 47%. There was a consistent improvement in Length of Stay in the PED, which decreased more than 60 minutes (from 5 hrs. 21 min. to 4 hrs. 29 min).There is a significant improvement of quality in the care of VOC including 1. Pain scoring system. 2. Documented pain reassessment. 3. Use of a multidisciplinary reviewed protocol that includes PED SCD VOC clinical pathway, and an updated order set power plan with IN Fentanyl as the first line. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The burden of sleep disordered breathing in children with sickle cell disease.

Children with sickle cell disease (SCD) have an increased risk of sleep disordered breathing (SDB) compared with the general pediatric population. There has been a growing research interest on this field in recent years, yet many questions regarding risk factors and clinical implications of SDB remain unclear. The aim of this review is to provide a concise narrative and systematic synthesis of the available evidence on the epidemiology, clinical presentation, complications, and management, of SDB in children with SCD. An electronic search was conducted on studies published from the 1st of January 2000 to the 31st of December 2020 in PubMed/Medline, Scopus, and Cochrane databases. All studies focusing on SDB in children with SCD aged from 0 to 20 years were included. Studies were eligible for inclusion if available in the English language. A quantitative synthesis of the included studies was performed. Only studies focusing on specific treatment outcomes were included in a meta-analytic process. A total of 190 papers were initially identified. After screening the title and abstract, 112 articles were evaluated for eligibility. At the end of the selection process, 62 studies were included in the analysis. Sleep disordered breathing is associated with worse neurological, neurocognitive, and cardiological outcomes, whereas the association with frequency or severity of vaso-occlusive pain events and acute chest syndrome was not clarified. Therapeutic interventions like adenotonsillectomy or oxygen supplementation may result in a significant increase in mean nocturnal oxygen saturation but effective clinical implications remain still unclear.

Indirect Economic Burden of Sickle Cell Disease

ObjectiveThis study aimed to quantify the indirect costs of sickle cell disease in the United States. MethodsAdult patients from a sickle cell disease clinic at an urban academic healthcare system completed an adapted Institute for Medical Technology Assessment Productivity Cost Questionnaire related to the impact of their disorder on absenteeism, presenteeism, ability to contribute through unpaid work outside of employment, and other aspects of life. Additional data were collected from patient records about each participant’s genotype, total hemoglobin level, and pain level. ResultsOf the 192 individuals, 187 who completed the survey reported experiencing vaso-occlusive crisis pain events during the last year that negatively affected their productivity at work and in daily roles. Three-fourths of respondents reported impairment in their ability to complete everyday tasks, such as caring for children, running errands, doing housework, shopping for groceries, and volunteer (unpaid) work. Only 30% of respondents reported being employed or self-employed. Of those employed, estimated costs of absenteeism and presenteeism attributable to pain events averaged $15 103 per person annually. Estimated total annual losses in unpaid work productivity averaged $3 145 862 for the study respondents and another $2 870 652 for their caregivers. ConclusionsSickle cell disease affected the work productivity, nonwork productivity, and the daily lives of adults seen with the disorder in an academic medical center.

Nitrous Oxide Gas May be a Promising Therapy for Acute Priapism in Patients with Sickle Cell Disease: A Case Report

▪Background : Nitrous oxide (N2O) is an inhalational medication that has anxiolytic, amnestic, potent venodilatory and mild-to-moderate analgesic properties commonly used in the emergency department (ED) setting. N2O has a rapid onset of action (<5 minutes) and recovery (< 5 minutes) and can be quickly titrated to effect without the need for IV access. It has few side effects, does not require renal or hepatic metabolism for excretion and has no reports of allergic reaction. Priapism is a serious complication of sickle cell disease (SCD) affecting approximately 35% of males, with an adverse impact on quality of life. Treatment options are limited and not evidence based, including hydration, alkalization, analgesia, oxygenation to prevent further sickling, and exchange transfusion. Patients who do not respond within 4 hours often require a painful invasive procedure that includes aspiration of blood from the corpus cavernosum and phenylephrine injections. Case reports have described a therapeutic benefit from oral pseudoephedrine, sildenafil, and IV arginine, however controlled clinical trials are lacking. Although a 50:50 nitrous oxide/oxygen mix is commonly used in France to enhance analgesia in patients with SCD and vaso-occlusive pain events (VOE) not sufficiently responding to IV morphine, there are no reports of its use to treat priapism.Objective: To describe the effects of N2O for the treatment of acute priapism associated with SCD in a pediatric ED.Methods: This is a case report of a child with Hb-SS who on 2 separate occasions presented to the ED with acute priapism that failed oral therapy (pseudoephedrine and opioids). On each occasion he received standard treatment for VOE pain based on institutional guidelines for SCD that included oral opioids and intranasal fentanyl prior to IV access. N2O gas was utilized to help facilitate IV catheter placement.Results: In each presentation (at ages 8 and 10 years) the patient experienced complete resolution of the priapism within 5-15 min of receiving N2O (max 60%). The patient was discharged from the ED following each presentation and had no recurrence during the subsequent week.Conclusions: Priapism is a challenging complication of SCD associated with long-term morbidity and a paucity of treatment options. Given the risks and inconsistent results of current recommended therapy, N2O may represent a potentially superior treatment option for priapism presenting to the ED that warrants further investigation. Although anecdotal, N2O inhalation is a safe consideration during a time when a treating ED physician has few alternatives. DisclosuresMorris:Pfizer: Consultancy; Lifetrients: Patents & Royalties: I am inventor of IP owned by USCF-Benioff Children's Hospital Oakland, licensed to Lifetrients, generating royalties; Nestle: Consultancy; Calithera Biosciences: Consultancy; MAST Therapeutics: Research Funding.

GBT1118 Diminishes Vaso-Occlusion in Sickle Cell Disease Mice

Recurrent, painful vaso-occlusive events are one of the most debilitating complications of sickle cell disease (SCD). The process involves occlusion of blood flow through small vessels by heterogeneous cell clusters comprised of red blood cells (RBCs), neutrophils, and platelets. Activated endothelial cells localize and facilitate vaso-occlusion. The central triggering event in the process is hemoglobin S (HbS) polymerization and the consequent damage to RBCs. Many recent clinical efforts to prevent vaso-occlusive events have focused on downstream events mediated by inflammatory molecules. The present work however studies the triggering event by assessing the direct impact of allosteric modulators of hemoglobin oxygen (Hb-O2) affinity on vaso-occlusion in a murine model of SCD.In this study, we used GBT1118 (a structural analog of GBT440) in a modified dorsal skin fold model in an HbSS knock-in mouse model of SCD (Townes; Wu et al., Blood 2006). GBT1118 binds covalently and reversibly via an imine intermediate to the N-terminal valine of the hemoglobin α chain, and allosterically increases the intracellular hemoglobin affinity for oxygen (Dufu et al., Am J Physiol Heart Circ Physiol 2017). The dorsal skin fold chamber model has been used previously to study vaso-occlusion in SCD mice (Kalambur et al., Am J Hematol 2004). In this present study, mice were treated acutely by oral gavage with GBT1118 or vehicle control in a blinded fashion. Two hours after drug treatment, a baseline of vascular patency at ambient air was established using intravital microscopy to count blood vessels with blood flow. Subsequently animals were exposed to 1 h hypoxia (7.0% oxygen) and 1 h reoxygenation at ambient air. At that time the previously observed blood vessels were monitored again, and the percentage of occluded vessels was recorded. We observed a significant reduction of vaso-occlusion in animals that had been treated with GBT1118 (p<0.05).In summary, while improved survival has been described in hypoxia-challenged SCD mice treated with allosteric modulators of hemoglobin (Abdulmalik et al., Br J Haematol 2005), our study demonstrates for the first time that a hemoglobin allosteric modulator can reduce vaso-occlusion in a mouse model of SCD. The protective effect elicited by GBT1118 may either be attributed to improved oxygenation or allosteric modulation of HbS. Both mechanisms may directly delay hypoxia-triggered polymerization of HbS, sufficiently for RBCs to transit the microcirculation without sickling, without adhering to vessel wall, and therefore without causing vaso-occlusion.The results of this study expand on the potential mechanisms by which allosteric modulators of Hb-O2 affinity may contribute to the treatment of SCD, in addition to previously described hematological benefits. DisclosuresAlt:Bayer: Equity Ownership; Global Blood Therapeutics: Employment, Equity Ownership. Liu:Global Blood Therapeutics: Employment. Li:Global Blood Therapeutics: Employment, Equity Ownership. Silva:Global Blood Therapeutics: Employment, Equity Ownership. Rademacher:Global Blood Therapeutics: Employment, Equity Ownership. Zou:Global Blood Therapeutics: Employment, Equity Ownership. Patel:Global Blood Therapeutics: Employment, Equity Ownership. Dufu:Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Kauser:Global Blood Therapeutics: Employment, Equity Ownership.

MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease

Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology. Dilution of HbS with nonsickling hemoglobin or hemoglobin with increased oxygen affinity, such as fetal hemoglobin or HbS bound to aromatic aldehydes, is clinically beneficial in decreasing polymerization. We investigated a novel alternate approach to modify HbS and decrease polymerization by inhibiting methionine aminopeptidase 2 (MetAP2), which cleaves the initiator methionine (iMet) from Val1 of α-globin and βS-globin. Kinetic studies with MetAP2 show that βS-globin is a fivefold better substrate than α-globin. Knockdown of MetAP2 in human umbilical cord blood–derived erythroid progenitor 2 cells shows more extensive modification of α-globin than β-globin, consistent with kinetic data. Treatment of human erythroid cells in vitro or Townes SCD mice in vivo with selective MetAP2 inhibitors extensively modifies both globins with N-terminal iMet and acetylated iMet. HbS modification by MetAP2 inhibition increases oxygen affinity, as measured by decreased oxygen tension at which hemoglobin is 50% saturated. Acetyl-iMet modification on βS-globin delays HbS polymerization under hypoxia. MetAP2 inhibitor–treated Townes mice reach 50% total HbS modification, significantly increasing the affinity of RBCs for oxygen, increasing whole blood single-cell RBC oxygen saturation, and decreasing fractional flow velocity losses in blood rheology under decreased oxygen pressures. Crystal structures of modified HbS variants show stabilization of the nonpolymerizing high O2–affinity R2 state, explaining modified HbS antisickling activity. Further study of MetAP2 inhibition as a potential therapeutic target for SCD is warranted.

Resolution of Serious Vaso-Occlusive Pain Crises and Reduction in Patient-Reported Pain Intensity: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Resolution of Serious Vaso-Occlusive Pain Crises and Reduction in Patient-Reported Pain Intensity: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Vaso-Occlusive Events Precipitated By Intraarticular Steroid Injections in Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is a group of inherited hemoglobin diseases (Hb), caused by a point mutation in the b-globin gene, that affects more than 100,00 people in the US and millions worldwide. No organ system is left unaffected by SCD, including the musculoskeletal system; complications which can greatly decrease quality of life and contribute to significant burden for these patients. Orthopedic complications include bone pain, dactylitis, growth retardation and atypical skeletal development, osteomyelitis and septic arthritis, bone demineralization, motor/mobility impairment, osteonecrosis and other causes of arthritis and rheumatologic disease. While surgical repair by arthroplasty is often a definitive solution to joint pain, conservative, non-operative treatments are first-line, including physical therapy and intraarticular corticosteroid injections. Corticosteroid injections can be used as a convenient outpatient solution to reduce inflammation and relieve pain without undergoing surgical measures. The use of steroids for non-orthopedic complications of SCD is not benign for many patients, and may be associated with the development of rebound vaso-occlusive pain events, requiring hospitalization, as well as hemorrhagic stroke. A review of the literature revealed two cases of patients with SCD who received intraarticular steroid injections for rheumatoid arthritis in whom the injections precipitated an acute vaso-occlusive episode that required admission. In view of these findings, we are interested in determining if any adults in our adult SCD clinic who had an intraarticular injection of a steroid developed worsening of pain. Methods: After approval by the UIC IRB, a retrospective chart review was conducted for subjects enrolled in the UIC Adult Sickle Cell Center treated with an intraarticular steroid injection. Data collected included: type of medication used, injection location, indication, pain complication and timeline of symptoms, admission, age, sex, genotype and BMI. Vaso-occlusive events described were unusually severe compared to the pre-corticosteroid clinical course and not reported with other triggers for SCD vaso-occlusive events. Results: Four patients were identified. Characteristics of these patients and injections are listed in table 1. Patients received one or more injections of knees, hips, wrists and fingers before recognizing the associated pain with the injection. Indications for injections included primary osteoarthritis, osteoarthritis secondary to avascular necrosis, tendonitis and tenosynovitis. All injections were a combination of local anesthetic and glucocorticoid. The majority of injections were 2 cc lidocaine 1%, 1 cc triamcinolone acetonide-40mg. Other local anesthetics used were xylocaine and bupivacaine. Discussion: With improvements in medical care, more people with SCD are surviving into adulthood and developing orthopedic complications of SCD, as well as aging, such as osteoarthritis. While the development of acute pain after treatment of the acute chest syndrome with steroids is known, there were only 2 reported cases of SCD patients who developed severe pain associated with intraarticular injections. We report here four additional cases of adults with SCD who received an injection and developed worsening of their pain, often requiring admission. While these numbers are small, we believe that this may be a much more common complication of steroid injections and providers should discuss this with their patients. The observations that are made in this study raise into question the idea that while temporary pain relief is the intended outcome, this is not the result in all patients- the fact of which should be a consideration made by all clinicians when offering steroid injections as opposed to non-steroid joint injections to patients with SCD. The pathophysiology behind this effect of steroid injections is unclear. In the event that a patient with SCD presents with pain symptoms, either worsening pain or pain uncharacteristic of their usual symptoms, a consideration for potential causes should be recent steroid injection for joint pain. These considerations may help guide clinical decision making. Disclosures No relevant conflicts of interest to declare.

Hydroxyurea to Reduce Stroke Risk in Tanzanian Children with Sickle Cell Anemia

Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with &amp;gt;300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease modifying therapy for SCA, is safe and feasible for low-resource and malarial endemic countries within sub-Saharan Africa and when used at maximum tolerated dose (MTD), decreases the incidence of acute painful vaso-occlusive events, infections, malaria, transfusions, hospitalizations, and death. Whether hydroxyurea can prevent primary stroke in SCA within Africa has not yet been determined, due in part to lack of stroke screening programs using transcranial Doppler (TCD) ultrasonography. If effective, hydroxyurea would have even more therapeutic benefits for children with SCA, particularly in settings where blood is not available, affordable, or safe. We designed the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial to determine the stroke risk among Tanzanian children using TCD screening and to investigate the effects of hydroxyurea to reduce that risk. Methods: The SPHERE trial (NCT03948867) is a single center prospective phase 2 open-label screening and treatment pilot study at Bugando Medical Centre, a teaching and referral hospital in Mwanza, Tanzania. Children 2-16 years old with SCA consented to TCD screening by locally trained and certified examiners; recent febrile illness, red cell transfusion, or hospitalization were temporary exclusions. Study participants with maximum Time-Averaged Mean Velocity (TAMV) on TCD exam categorized as conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) are offered hydroxyurea with escalation to MTD, while those with normal TCD screening exams will be rescreened annually. Hydroxyurea is initiated at ~20 mg/kg/day using 500 mg capsules and a weekly dosing calculator, then escalated every 8 weeks by 5 mg/kg/day up to 35 mg/kg/day. Children on hydroxyurea are seen monthly during dose escalation and every 3 months after reaching MTD. The primary endpoint is change in TCD velocity after 12 months of hydroxyurea therapy. Secondary endpoints include changes in splenic volume and filtrative function; change in renal function; incidence of infection, especially malaria; hydroxyurea pharmacokinetics; and genetic modifiers of disease including pharmacogenomics. Results: From April 2019 to April 2020, a total of 202 children underwent TCD screening, exceeding the projected enrollment pace and goal (Figure). The average age (mean ± SD) at enrollment was 6.8 ± 3.5 years, and 53% were female. A majority had previous dactylitis (75%), painful vaso-occlusive episode (93%), blood transfusion (68%), and malaria (89%). Recurrent hospitalization was common with 30% having &amp;gt;5 previous hospitalizations. Only 4% had previously used hydroxyurea. Baseline labs included hemoglobin = 7.8 ± 1.3 g/dL, HbF = 9.3 ± 5.4 %, and ANC = 5.5 ± 2.4 x 109/L. Baseline assessment revealed a palpable spleen in 46 children (23%), and most of these (29) were ≥5 cm below the costal margin. Abdominal ultrasonography documented splenic tissue in 91% of children with an average volume of 101 ± 123 mL (range 8-1045). TCD examinations were performed in all children at enrollment with average TAMV of 148 ± 27 cm/sec [median 144, IQR 130-169 cm/sec] with 76% normal, 21% conditional, 2% abnormal, and 1% inadequate exams. Of 47 children eligible for hydroxyurea for elevated TCD velocities, 45 successfully initiated treatment, while 1 lived too far away for regular visits, and 1 had low blood counts from acute splenic sequestration and died before initiating study treatment. Conclusion: Children with SCA in Tanzania have a high risk for primary stroke. Identification of elevated TCD velocities through screening by local trained certified examiners, coupled with initiation of hydroxyurea treatment with dose escalation to MTD, offers a feasible and affordable means by which to lower TCD velocities and reduce primary stroke risk. Now fully enrolled, SPHERE has built local clinical capacity, research infrastructure and high-quality TCD screening, and will prospectively determine the benefits of hydroxyurea for stroke prevention, as a prelude for expanding hydroxyurea access for children with SCA in Tanzania. Figure Disclosures No relevant conflicts of interest to declare.

Long-term oxygen therapy in children with sickle cell disease and hypoxaemia

ObjectiveTo evaluate the acceptability and safety profile of nocturnal long-term oxygen therapy (LTOT) in children with sickle cell disease (SCD) and chronic hypoxaemia.DesignRetrospective cohort study.Patients, setting and interventionChildren with SCD...

Hematologist and transplant physicians: How and where to meet for the best of sickle cell disease patients?

Despite huge progress in the fields of newborn screening, encapsulated bacterial infection prophylaxis, immunization, and supportive care in general, people suffering from sickle cell anemia still continue to have a shorter life expectancy and a poorer quality of life due to painful vaso-occlusive events and strokes during childhood, and later, cardiac, pulmonary, and renal injuries, including in Western and high-income countries.From the 2000s, allogeneic stem cell transplantation for severe sickle cell disease from a sibling donor provided the best results—overall as well as disease-free survival—never obtained for any other disease. Nevertheless, this only curative option is proposed to few patient numbers, including in Western countries with high-level medical equipment development, with discrepancies between (i) patients and family, (ii) physicians and care centers dedicated to sickle cell disease, and (iii) hematopoietic stem cell transplant teams.Due to these discrepancies and in order to provide the same quality of discussion and treatment choice for every sickle cell disease patient, we developed a National French multidisciplinary pluri-annual meeting dedicated to sickle cell disease patients and transplantation. We report here our experience of such a meeting.